Red Gold: In vitro Generation of Red Blood Cells

 

It’s a liquid that is far more valuable than gold, perhaps the very source of life. How many times have you heard the cry for blood donation? In the last decade, demands for donation have skyrocketed in order to maintain a sufficient supply [1]. In disaster situations all around the world, blood supply shortage is a worry at the forefront of rescue operations. At the moment the only way to replenish red blood cells (RBCs) is by transfusion from one person to another. Despite many advances, our current knowledge of differentiation and amplification of blood stem cells into red blood cells is limited and we are incapable of synthesizing blood in vitro. By understanding hematopoietic stem cell (HSC) differentiation within the bone marrow, specifically the cocktail of transcription factors at work, we can realize the potential of HSCs and their ability to reconstitute the entire blood system of an organism, thereby potentially making blood drives a relic of the past [2].

HSCs rest in the bone marrow. They are responsible for directing progenitor cells, cells in a stage prior to maturity, that eventually lose differentiation potential and become mature blood cells. Of the various blood cells that can potentially be produced, including those blood cells involved in immune response, erythrocytes (red blood cells) are the cells currently under focus [2, 3]. Although there is tremendous potential in understanding the mechanisms of hematopoietic stem cells, there is social controversy about the use of stem cells in scientific research.

Some proponents of the pro-life platform call for stopping the use of stem cells, specifically embryonic stem cells (ESCs) due to their fundamental involvement in the creation of life. However, the 2012 recipients of the Nobel prize in medicine, Shinya Yamanaka and John Gurdon, have brought light to the potential for converting mature cells into stem cells [4]. By taking differentiated human adult cells and a set of identified transcription factors, we can reprogram these cells to a state of pluripotency, virtually rendering them embryonic stem cells for all experimental purposes. By avoiding the conflict associated with embryonic stem cells, as well as understanding the significance and rarity of certain necessary stem cells we can design a system to enable personalized red blood cell production outside of a living system.

Current research in Leonard I. Zon’s lab reveals that zebrafish may be an ideal model for understanding HSC differentiation and erythropoiesis in human systems. Zebrafish, Danio rerio, is an excellent model organism due to its short generation time, high fecundity, external fertilization, small size and transparency of embryos, and the availability of genetic tools [3]. By utilizing a transgenic line of bloodless zebrafish mutants, the Zon lab hopes to understand and reconstitute the missing blood system, using various chemical suppressor screen models and genetic techniques which will enable the discovery of the transcriptional framework and mechanisms involved in erythropoiesis. The study recognizes the importance of RBC precursors and is attempting to reconstitute the biochemical integrity of pathways present in normal, wild type zebrafish [5].

The implications of this research extend far beyond the generation of blood outside of a living system. If the mechanistic nuances of erythropoiesis were to be understood sufficiently through these experiments with bloodless zebrafish mutant, research in treating blood borne illnesses like anemia, leukemia, and myelodysplasia would be bolstered. By understanding the underlying reasons behind the formation of not only erythrocytes during differentiation, but the entire spectrum of cells produced by HSCs, there is potential for mapping out the genesis of blood borne diseases and generating therapies targeted towards the specific processes within these pathways which either give rise to or sustain life-threatening illnesses. Such a discovery would eventually enable the production of personalized medicine aimed at targeting a specific cause for an ailment rather than taking the usual shotgun approach and nonspecifically altering biochemical processes in order to obtain the desired effect. Essentially, approaches to blood borne diseases would be proactive rather than reactive. With the aforementioned usefulness of the Zebrafish model, there is great potential for the use of in vivo drug discovery techniques through toxicological studies and disease modeling relative to the pathways of HSC differentiation [6, 7].

Consider that we do end up finding the mechanism for developing RBCs in vitro. What sort of social implications would this have on the administration of medicine, public health policy, and development at an international scale? With the current knowledge available on the various forms of blood borne illnesses and contaminants, blood drives have become more stringent in outlining their criteria for blood safety. With such selectivity, blood collection has been significantly slower all across the world. By defining those individuals that are eligible and those that are not, we are severely limiting the availability of supplies even under emergency conditions. These issues, among others like donor retention and understanding the planned behavior of individuals choosing to donate blood) would no longer be of importance under a plentiful supply of synthetically generated blood [1].

In a social context, the donation of blood is seen as an altruistic act performed voluntarily by one individual without any immediate or even long term benefit. Yet at an economic level, should blood be “banked” and treated as a commodity due to its scarcity? Even though the rate of blood donation has risen in recent years, so has the need [8]. The limitations of blood generation technology are rooted in the industrial processes and wastes associated with its production. In the same sense, an institutionalization of blood production and control would entail a privatization of blood. With a palpable and reproducible process of blood generation, many existing biotech competitors would be vying for control of the “blood market.” Such controversies could present considerable challenges to bridging the gap between blood production and commercial distribution.

With the production of viable red blood cells still a ways off, existing technology consists primarily of blood substitutes rather than sustainable permanent solutions.  The primary function of blood substitutes is to provide a temporary means of oxygenating tissue in circumstances like surgeries or trauma settings. This technology exists in the form of hemoglobin-based oxygen carriers and perfluorocarbons (PFCs). These forms of artificial blood are meant to fill the gap of time between a significant loss of blood and the point at which the recipient’s body compensates [9]. Nonetheless, both forms have not been clinically approved due to adverse side effects including difficulty swallowing, jaundice, skin discoloration, and abnormally fast resting heart rate noted in patients [10]. Consequently, the usefulness of blood substitutes relative to authentic RBCs is limited, especially on a larger scale.

Ultimately, we see that the future of in vitro generation of red blood cells is contingent upon the success of determining the mechanistic nuances and transcriptional framework in the pathways leading from hematopoietic stem cell generation to erythrocyte. With a viable supply of RBCs, blood drives may be rendered obsolete; moreover personalized care of blood borne illnesses would allow for new platforms of drug discovery and health policy.

References

    1. Masser, B.M., et al. “The psychology of blood donations: current research and future directions.” Transfusion Medicine Review (2008): 215-233.
    2. Orkin, S.H. and L.I. Zon. “Hematopoiesis: an evolving paradigm for stem cell biology.” Cell (2008): 631-644.
    3. de Jong, J.L. and L.I. Zon. “Use of the zebrafish system to study primitive and definitive hematopoiesis.” Annual review of genetics 39 (2005): 481.
    4. “Shinya Yamanaka wins 2012 nobel prize in medicine.” http://www.ucsf.edu/news/2012/10/12898/shinya-yamanaka-wins-2012-nobel-prize-medicine
    5. Bai, X. et al. “TIF1gamma controls erythroid cell fate by regulating transcription elongation.” Cell (2010) 142: 133.
    6. van Raalte, D.H. et al. “Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future.” Pharmaceutical research 21 (2004): 1531.
    7. Zon, L.I. and R.T. Peterson. “In vivo drug discovery in the zebrafish. Nature reviews.” Drug discovery 4 (2005): 35.
    8. “Red Cross Blood Supply Drops to Critically Low Levels.” American Red Cross. http://www.heraldextra.com/news/local/american-red-cross-blood-supply-levels-critically-low/article_f91662bd-0756-5f47-9d5c-e969c32c9c6a.html
    9. Schimmeyer, S. “The search for a blood substitute.” Illumin 1 (2002). Accessed November 7, 2012. http://illumin.usc.edu/58/the-search-for-a-blood-substitute/
    10. Henkel-Hanke, T. and M. Oleck. “Artificial oxygen carriers: a current review.” AANA Journal (2007): 205-211.
    11. Takahashi, K. and S. Yamanaka. “Induction of pluripotent stem cells from mouse embryonic and adult fribroblsat cultures by defined factors.” Cell (2006): 663-676.

Image Credit: 33rd Square
Image Credit: Integrative Biology

Wahaj is a sophomore at Harvard College and plans on concentrating in Human Developmental and regenerative Biology with a secondary in Global Health and Health Policy. Wahaj is interested in studying the applicability of stem cell technology in drug discovery and artificial blood generation in vitro and hopes to one day create sustainable and viable red blood cells for delivery to patients. Follow The Triple Helix Online on Twitter and join us on Facebook.